1. Technical Field
This description pertains generally to medical imaging, and more particularly to functional brain imaging.
2. Background Discussion
Brain tissue is made of an assembly of interconnected cells called neurons that express activity by means of short electrical pulses called action-potentials. Functional brain imaging designates any device or method that is capable of detecting these pulses, directly or indirectly in order to better understand the architecture and observe the behavior of live neural networks. Primary criteria for evaluating functional brain imaging methods are: a) scale, i.e. the ability to quantify activity in many neurons simultaneously in a large volume; b) high spatial resolution, i.e. the ability to measure activity at the scale of a single neuron; c) high temporal resolution, i.e. the ability to separate individual action-potentials; d) non-invasive acquisition for minimally disturbing cell behavior; and e) accuracy, particularly with ability to operate, even in deep layers of brain tissue, where optical scattering effects are significant.
One example of a non-invasive, commercially available, functional brain activity measuring technique is Functional Magnetic Resonance Imaging (fMRI) adapted to monitor activity in full 3D brains, and preferred for very large brains. However, this method observes blood flow instead of directly targeting neurons, leading to poor spatial and temporal resolution.
Other current techniques take advantage of the recent development of engineered calcium-activated fluorescence proteins (e.g. GCaMP) and voltage sensitive dyes for higher spatial resolution. However, they use mechanical scanning to reduce aberrations caused by optical scattering and offer good spatial resolution at the expense of temporal resolution. For instance, two-photon microscopy relies on a nonlinear effect to locally excite fluorescence in a diffraction-limited spot that can be scanned along 3 dimensions. The excitation is obtained with high power laser sources in the infrared domain, which is significantly less scattered by brain tissue. Two-photon microscopy provides high resolution images in 3D, but requires fast controlled mechanical scanning which considerably limits temporal resolution.
Another existing technique is Light-Sheet Microscopy, which uses patterned fluorescence illumination, and one scanning axis to selectively target the excitation light along one specific depth level. It is significantly faster than two-photon methods, but still limited to observing one focal depth level at a time. It requires access to the sample from one or two sides, 90 degrees away form the optical axis of the imaging path. Alternative options with a single microscope objective are possible, at the expense of an additional loss in resolution.
Light field microscopy is a further advancement that uses a micro-lens array in the imaging path of a microscope to capture both position and direction of incoming light on a single frame. Acquisition is followed by a computational ray-tracing inversion, or a de-convolution step to reconstruct a volume image. Volume image reconstruction has been implemented for functional brain imaging but existing techniques are unable to correct for optical scattering. Consequently, volume image reconstruction through thick brain tissue leads to blurred reconstructions and losses of information, and the shape of individual neurons can not be reconstructed accurately.
Accordingly, an object of the present description are functional brain imaging systems and methods that provide accurate, non-invasive quantitative recordings of neural activity, simultaneously in a large volume, with high spatial resolution, and high temporal resolution.